The present invention relates to a series of novel heterocyclic compounds having a saturated heterocyclic ring containing two ring nitrogen atoms, one of which is substituted by a halobenzhydryl group and the other of which is substituted by specific substituted alkyl groups. The invention also provides a pharmaceutical composition for the treatment, inter alia, of disorders affecting circulation within the brain, and also provides methods of using the compounds and processes for preparing them.
Maintenance of a good blood circulation is absolutely vital to continued good health in humans and other animals, and many compounds, of the class known generally as "vasodilators", have been used or proposed to be used to assist the circulation of the blood and/or to relieve symptoms arising from poor circulation. However, one of the most damaging and distressing consequences of circulatory problems is damage to the brain, which may be non-fatal but irreversible and can have serious effects on the personality and behavior of the patient. Similar problems may also arise from other ischemic events, which may or may not be the consequence of circulatory disorders. Unfortunately, relatively few of the many vasodilators available are indicated for use in the treatment of cerebral vascular insufficiency.
In accordance with the present invention, we have now discovered a series of new compounds which have shown exciting possibilities for the treatment of cerebral vascular disorders. The new compounds of the invention are characterized by a saturated heterocyclic ring containing two ring nitrogen atoms (e.g. an imidazolidine, piperazine or homopiperazine ring), one of the nitrogen atoms having a halobenzhydryl substituent and the other having a substituent comprising an alkyl group, itself having certain specific substituents thereon.
Of the several compounds which have been proposed for use in the treatment and prophylaxis of cerebral vascular disorders, the two compounds which most closely resemble those of the present invention, in terms both of molecular structure and pharmacological effects, are flunarizine (which itself was developed fros: the closely related drug cinnarizine) and cinepazide. Flunarizine and cinepazide are described in The Merck Index, Tenth Edition, published by Merck & Co. Inc.. 1983, in monographs 4045 and 2267 respectively. These compounds are included amongst the compounds covered by United Kingdom Patents No. 1 268 710 and 1 218 591, respectively. Flunarizine has the formula (A) given below, whilst cinepazide has the formula (B): ##STR1##
In the above formulae, Me represents the methyl group.
These compounds are known to be calcium-entry blockers, i.e. they block or reduce the entry of calcium (as Ca.sup.2+) into cells of the animal body. Calcium buildup in vulnerable brain cells has been shown to have a significant correlation with irreversible cell damage, and thus compounds which can reduce the entry of calcium into these cells can be expected to assist in the prevention of such damage. Calcium buildup in cells can be caused by ischemia (i.e. an inadequate supply of oxygen to the organ or part of the body containing the cells), and calcium-entry blockers, such as flunarizine and cinepazide, have been found to give a degree of protection against the deleterious effects of ischemia, even when the drug is administered after the onset of ischemia.
We have now discovered a series of new compounds structurally related to flunarizine, but which have significantly better pharmacological effects. In particular, they improve blood circulation, especially in the brain, are excellent selective calcium-entry and overload blockers and confer a significant degree of protection against morbidity arising from reduced oxygen intake, e.g. as a result of breathing an oxygen-poor atmosphere. Moreover, the compounds of the present invention have shown a significantly lower toxicity than do the prior art compounds.